Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women

Abstract

Objectives Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. Methods Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M / 8F) (400mg/day) or placebo (14M / 9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5–7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. Results Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. Conclusions As expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence.

Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats

“…A recent study in humans by Milivojevic et al (2016) showed similar results, as allopregnanalone, a metabolite of progesterone, improved Stroop performance, a measure related to impulsive action. However, the beneficial effects of PRO may be specific to this particular subtype of impulsivity, as recent evidence from our laboratory showed no effect of PRO on impulsive choice for sucrose pellets in females and males, measured by a delay discounting task (Smethells et al, 2016).…”

“…Milivojevic et al (2016) showed no sex differences in a measure of inhibitory control in humans. Anker et al (2008) also reported similar baseline rates of responding across males and females in impulsive action for sucrose pellets using a modified (i.e., extinction) No-Go component.…”

“…Exogenously-delivered PRO is effective for treating stimulant abuse in animals (Anker et al, 2009; Zlebnik et al, 2014; Evans and Foltin, 2010) and may have potential as a stimulant cessation agent in humans (Fox et al, 2013; Evans and Foltin, 2006; for review, see Quinones-Jenab and Jenab, 2010; Evans and Foltin, 2010; Carroll and Lynch, 2016; Carroll and Smethells, 2016). A recent report indicated that PRO and its metabolites (allopregnanalone) reduce stress and impulsive behavior as measured by the Stroop test in humans (Milivojevic et al, 2016). However, the effect of PRO on treating underlying behaviors such as impulsive action that have been implicated in drug abuse in rats is currently unknown.…”

Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders

“…In a follow-up study, we measured basal levels of the neurosteroid ALLO while on 5 days of progesterone versus placebo to assess if progesterone effects in this study were due to increased levels of ALLO. Indeed, we found that the high ALLO group (treated with progesterone) versus the low ALLO group showed reduced overall drug and alcohol craving, improved Stroop performance, and both reductions in basal cortisol levels as well as increased cortisol in response to stress (Milivojevic et al, 2016). While there are no direct data on neurosteroid treatment in alcohol dependent individuals, these data support our notion that compounds and approaches that normalize HPA axis function need to be explored to fully test whether addressing this stress-related pathophysiology in alcohol use disorders with specific targeted treatments may be helpful in improving alcoholism relapse and recovery outcomes.…”

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward

“…For example, COC’s rewarding stimulant effects seen in the follicular phase could have been counteracted by PRO’s anxiolytic effects (Nyberg et al 2006; Schneider and Popik 2007) to reduce intake during the follicular phase. In contrast, higher PCP intake in the luteal phase may have been due to alleviation of dysphoric effects of PCP by putative anxiolytic effects of PRO (Llaneza and Frye 2009; Schneider and Popik 2007) or its metabolite, allopregnanolone (ALLO) (Milivojevic et al 2016). Elevated PRO did not decrease cocaine self-administration in previous studies (Mello et al 2007; Cooper et al 2013), but exogenously-administered PRO decreased cocaine self-administration in female rhesus monkeys (Mello et al 2011).…”